The central goal of insulin replacement therapy in the treatment of Type 1 diabetes mellitus (T1DM) is tight control of blood glucose concentration. This Phase I STTR application, submitted by Thermalin Diabetes, Inc., in conjunction with Case Western Reserve University, seeks support for the pre-clinical testing and commercial development of an ultra-stable and ultra-fast-acting insulin analog for use in insulin pumps. The novel physico- chemical features of this insulin analog (designated Thermalin) promise to make feasible the long-term use of implantable intraperitoneal insulin pumps. This technology promises to enhance the safety and efficacy of insulin replacement therapy. Clinical trials have established the potential of implantable insulin pumps in the treatment of diabetes mellitus, but such pumps are presently regarded experimental by the FDA. A major problem is posed by the limited stability of present insulin formulations as stored for 1-3 months within the pump reservoir at 37oC within the peritoneal cavity. Such instability causes aberrant protein aggregation, which frequently impairs insulin delivery due to partial or complete obstruction of the pump. This problem is more severe with use of rapid- acting insulin analogs (HumalogTM (Lilly) and NovalogTM (Novo-Nordisk)), whose favorable pharmacokinetic properties otherwise offer significant advantages for use in external insulin pumps. Thermalin is a monomeric single-chain insulin analog refractory to aggregation and degradation in vitro for >6 months on agitation at 37oC. Whereas its thermodynamic stability is markedly higher than wild-type human insulin or insulin analogs currently approved for human use, the receptor-binding affinity of Thermalin and its biological activity in diabetic rat model of Type I diabetes mellitus are essentially identical to that of wild-type human insulin. No adverse increase in cross-binding to the IGF receptor or aberrant mitogenicity in cell culture is observed. These preliminary results strongly suggest that Thermalin will prove to be a "perfect pump insulin" for an implantable system, combining rapid pharmacokinetics with long-term stability at high protein concentration as stored in a pump reservoir with gentle agitation at 37oC. Design of Thermalin was based on general principles of biophysical chemistry together with analysis of the structure of insulin and its pathways of non-native aggregation and chemical degradation. Support is requested for the GLP manufacture of Thermalin in quantities (10 grams) sufficient (a) to permit rigorous testing of its chemical and physical stability and (b) to enable in vivo assessment of its potency, pharmacokinetics, and pharmacodynamics in pigs, a standard model for studies of insulin analogs. PUBLIC HEALTH RELEVANCE: We propose to develop an ultra-stable and ultra-fast-acting insulin analog for use in implantable insulin pumps. With this technology, patients with Type I diabetes mellitus may need only 3 or 4 injections per year (to refill the pump reservoir) rather than 3 or 4 injections per day. Whereas existing insulin formulations tend to degrade at body temperature over a period of weeks, often obstructing the pump, our product (designated "Thermalin") is stable for more than 6 months and is predicted to have both optimal durability and optimal rapid action for long-term implantable pump therapy.